U.S. patent number 10,435,351 [Application Number 15/882,498] was granted by the patent office on 2019-10-08 for enamide process.
This patent grant is currently assigned to SUNOVION PHARMACEUTICALS INC.. The grantee listed for this patent is SUNOVION PHARMACEUTICALS INC.. Invention is credited to John R. Snoonian, Charles P. Vandenbossche.
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United States Patent |
10,435,351 |
Vandenbossche , et
al. |
October 8, 2019 |
**Please see images for:
( Certificate of Correction ) ** |
Enamide process
Abstract
A convenient method for converting oximes into enamides is
disclosed. The process produces enamides without the concomitant
production of a large volume of metallic waste. ##STR00001## The
enamides are useful precursors to amides and amines.
Inventors: |
Vandenbossche; Charles P.
(Waltham, MA), Snoonian; John R. (Bolton, MA) |
Applicant: |
Name |
City |
State |
Country |
Type |
SUNOVION PHARMACEUTICALS INC. |
Marlborough |
MA |
US |
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Assignee: |
SUNOVION PHARMACEUTICALS INC.
(Marlborough, MA)
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Family
ID: |
62977157 |
Appl.
No.: |
15/882,498 |
Filed: |
January 29, 2018 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20180215702 A1 |
Aug 2, 2018 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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62452608 |
Jan 31, 2017 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07C
233/91 (20130101); C07C 231/12 (20130101); C07C
251/38 (20130101); C07C 249/08 (20130101); C07C
231/14 (20130101); C07C 209/50 (20130101); C07C
209/62 (20130101); C07C 231/10 (20130101); C07C
233/05 (20130101); C07C 231/10 (20130101); C07C
233/05 (20130101); C07C 249/08 (20130101); C07C
251/44 (20130101); C07C 249/08 (20130101); C07C
251/38 (20130101); C07C 209/50 (20130101); C07C
211/56 (20130101); C07C 2602/10 (20170501); C07B
2200/07 (20130101); C07C 2601/14 (20170501) |
Current International
Class: |
C07C
231/10 (20060101); C07C 249/08 (20060101); C07C
209/50 (20060101); C07C 233/91 (20060101); C07C
231/12 (20060101); C07C 209/62 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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2257518 |
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Mar 2016 |
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EP |
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99/18065 |
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Apr 1999 |
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WO |
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2007056403 |
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May 2007 |
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WO |
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2007/115185 |
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Oct 2007 |
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WO |
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Other References
Saha ("Directing Group Assisted Nucleophilic Substitution of
Propargylic Alcohols via o-Quinone Methide Intermediates: Bronsted
Acid Catalyzed, Hlhgly Enantio- and Diastereoselective Synthesis of
7-Alkynyl-12a-acetamido-Substituted Benzoxanthenes" Org Lett, 2015,
p. 648-651, including SI p. S1-S101). (Year: 2015). cited by
examiner .
International Search Report and WOISA from PCT/US18/15730 dated
Mar. 5, 2018. cited by applicant .
Tschaen, et al., Asymmetric Synthesis of MK-0499, American Chemical
Society, J. Org. Chem., vol. 60, pp. 4324-4330, 1995. cited by
applicant .
Savarin, et al., Direct N-Acetyl Enamine Formation: Lithium Bromide
Mediated Addition of Methyllithium to Nitriles, American Chemical
Society, Organic Letters, vol. 8, No. 18, pp. 3903-3906, 2006.
cited by applicant .
Reeves, et al., Direct Titanium-Mediated Conversion of Ketones into
Enamides with Ammonia and Acetic Anhydride, Angewandte
Communications, Agnew Chem. Int. Ed., vol. 51, pp. 1400-1404, 2012.
cited by applicant .
Klapars, et al., Preparation of Enamides via Palladium-Catalyzed
Amidation of Enol Tosylates, American Chemical Society, Organic
Letters, vol. 7, No. 6, pp. 1185-1188, 2005. cited by applicant
.
Lindhardt Hansen, et al., Fast and Regioselective Heck Couplings
with N-Acyl-N-vinylamine Derivatives, American Chemical Society, J.
Org. Chem., JOC Article, vol. 70, pp. 5997-6003, 2005. cited by
applicant .
Burk, et al., A Three-Step Procedure for Asymmetric Catalytic
Reductive Amidation of Ketones, American Chemical Society, J. Org.
Chem., vol. 63, pp. 6084-6085, 1998. cited by applicant .
Boar, et al., A Simple Synthesis of Enamides from Ketoximes, J.C.S.
Perkin I, pp. 1237-1241. Dec. 5, 1974. cited by applicant .
Barton, et al., A Further Synthesis of the Corticosteroid Side
Chain starting with a Suitable 17-Ketone, J. Chem. Soc., Perkin
Trans., pp. 2191-2192, 1985. cited by applicant .
Savarin, et al., Novel Intramolecular Reactivity of Oximes:
Synthesis of Cyclic and Spiro-Fused Imines, American Chemical
Society, Organic Letters, vol. 9, No. 6, pp. 981-983, 2007. cited
by applicant .
Zhao, et al., An Efficient Synthesis of Enamides from Ketones,
American Chemical Society, Organic Letters, vol. 10, No. 3, pp.
505-507, 2008. cited by applicant .
Takai, et al., Generation of chromioenamines by reduction of
O-acetyloximes with chromium (II) and their application, The Royal
Society of Chemistry, Chem. Commun., pp. 1724-1725, 2001. cited by
applicant .
Tang, et al., A Facile and Practical Synthesis of N-Acetyl
Enamides, American Chemical Society, J. Org. Chem., vol. 74, pp.
9258-9530, 2009. cited by applicant .
Boivin, et al., A New Method for the Generation and Capture of
Iminyl Radicals, Elsevier Science Ltd., Tetrahedron Letters, vol.
40 , pp. 4531-4534, 1999. cited by applicant .
Guan, et al., Synthesis of Enamides via Cul-Catalyzed Reductive
Acylation of Ketoximes with NaHSO.sub.3, American Chemical Society,
J. Org. Chem., JOC Note, vol. 76, pp. 339-341, 2011. cited by
applicant .
Deb, et al., Phenanthridine Synthesis through Iron-Catalyzed
Intramolecular N-Arylation of O-Acetyl Oxime, American Chemical
Society, Organic Letters, vol. 15, No. 16, pp. 4254-4257, 2013.
cited by applicant .
Guan, et al., Synthesis of Enamides via Rh/C-Catalyzed Direct
Hydroacylation of Ketoximes, American Chemical Society, Organic
Letters, vol. 11, No. 2, pp. 481-483, 2009. cited by applicant
.
Murugan, et al., An efficient preparation of N-acetyl enamides
catalyzed by Ru(II) complexes, Elsevier Ltd., Tetrahedron, vol. 69,
pp. 268-273, 2013. cited by applicant.
|
Primary Examiner: Bonaparte; Amy C
Attorney, Agent or Firm: Heslin Rothenberg Farley &
Mesiti, P.C. Hansen; Philip
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority to U.S. provisional application
62/452,608, filed Jan. 31, 2017. The entire contents of U.S.
62/452,608 are incorporated herein by reference.
Claims
What is claimed:
1. A process for converting an oxime to an enamide, said process
comprising contacting said oxime with an acyl donor and a phosphine
in the presence of an iron reagent that provides from 10 to 2000
ppm iron based on weight of iron in the iron reagent to weight of
the corresponding ketone of the oxime under conditions that convert
said oxime to said enamide.
2. The process according to claim 1 wherein the acyl donor is
acetic anhydride.
3. The process according to claim 1 wherein the phosphine is chosen
from tri n-butylphosphine, triethyl phosphine,
1,2-bisdiphenylphosphinoethane and triphenyl phosphine.
4. The process according to claim 3 wherein the phosphine is
triethyl phosphine.
5. The process according to claim 1 wherein the iron reagent is
chosen from elemental iron and Fe(II) salts and Fe(III) salts
wherein the counter ion is halide or alkanoate.
6. The process according to claim 5 wherein the iron reagent is
chosen from FeCl.sub.2 and Fe(OAc).sub.2.
7. The process according to claim 1 wherein said iron reagent
provides from 10 to 100 ppm iron.
8. The process according to claim 1 wherein said iron reagent
provides from 10 to 50 ppm iron.
9. The process according to claim 1 wherein said iron reagent
provides from 25 to 100 ppm iron.
10. The process according to claim 1 wherein said iron reagent
provides from 500 to 2000 ppm iron.
11. The process according to claim 1 wherein said process is
carried out in a solvent at a temperature between 80.degree. C. and
150.degree. C.
12. The process of claim 11 wherein said solvent is toluene.
13. The process according to claim 1 wherein the oxime is an oxime
of an aliphatic ketone.
14. The process according to claim 1 wherein the oxime is a
tetralone an oxime of a tetralone.
15. A process for converting a ketone to an enamide, said process
comprising the sequential steps of: (a) reacting said ketone with
hydroxylamine to provide an oxime; and (b) reacting said oxime with
an acyl donor and a phosphine in the presence of an iron reagent
that provides from 10 to 2000 ppm iron based on weight of iron in
the iron reagent to weight of the ketone.
16. A process for converting a prochiral ketone to an
enantiomerically enriched chiral amide, said process comprising:
(a) reacting said ketone with hydroxylamine to provide an oxime;
(b) reacting said oxime with an acyl donor and a phosphine in the
presence of an iron reagent that provides from 10 to 2000 ppm iron
based on weight of iron in the iron reagent to weight of the ketone
to provide an enamide; and (c) reducing said enamide with hydrogen
in the presence of a chiral catalyst to produce an enantiomerically
enriched chiral amide.
17. A process for converting a prochiral ketone to an
enantiomerically enriched chiral amine, said process comprising:
(a) reacting said ketone with hydroxylamine to provide an oxime;
(b) reacting said oxime with an acyl donor and a phosphine in the
presence of an iron reagent that provides from 10 to 2000 ppm iron
based on weight of iron in the iron reagent to weight of the ketone
to provide an enamide; (c) reducing said enamide with hydrogen in
the presence of a chiral catalyst to produce an enantiomerically
enriched chiral amide; and (d) hydrolyzing said chiral amide to an
enantiomerically enriched chiral amine.
18. The process of claim 15 wherein the acyl donor is acetic
anhydride, the phosphine is triethyl phosphine and the iron reagent
is chosen from FeCl.sub.2 and Fe(OAc).sub.2.
19. The process of claim 16 wherein the acyl donor is acetic
anhydride, the phosphine is triethyl phosphine and the iron reagent
is chosen from FeCl.sub.2 and Fe(OAc).sub.2.
20. The process of claim 17 wherein the acyl donor is acetic
anhydride, the phosphine is triethyl phosphine and the iron reagent
is chosen from FeCl.sub.2 and Fe(OAc).sub.2.
21. The process of claim 15 wherein steps (a) and (b) are carried
out without isolation of the oxime.
22. The process of claim 16 wherein steps (a) and (b) are carried
out without isolation of the oxime.
23. The process of claim 17 wherein steps (a) and (b) are carried
out without isolation of the oxime.
Description
FIELD
Methods of preparing compounds using an iron catalyst, and related
intermediates, are disclosed.
BACKGROUND
Enantiomerically-enriched chiral primary amines are commonly used
as resolving agents for racemic acids, as chiral auxiliaries for
asymmetric syntheses, and as ligands for transition metal catalysts
used in asymmetric catalysis. In addition, many pharmaceuticals
contain chiral amine moieties. Effective methods for the
preparation of such compounds are of great interest to the
pharmaceutical industry. Particularly valuable are processes that
allow for the preparation of each enantiomer or diastereomer in
enantiomeric excess (ee) or diastereomeric excess (de), as
appropriate, from prochiral or chiral starting materials.
As a result of the large number of chiral catalysts which are now
commercially available, chiral amines can be easily obtained from
the catalytic asymmetric hydrogenation of N-acyl enamines
(enamides). The preparation of an enantiomerically-enriched amine
via conversion of a precursor oxime to the corresponding enamide,
which is subsequently converted to the amine through asymmetric
hydrogenation and deprotection, has been described in WO 99/18065.
The oxime-to-enamide conversion process of WO 99/18065 is, however,
not of general applicability to a wide range of substrates.
Moreover, many of the recognized processes require a large excess
of metallic reagent to effect the conversion. For example, Burk et
al. [J. Org. Chem., 1998, 63, 6084] reported that enamides could be
prepared in 30-80% yield by heating the oxime in toluene at
70.degree. C. in the presence of 3.0 eq. of acetic anhydride and
2.0 eq. of iron powder. However, this method is unsuitable for
large scale manufacture because (a) it generates large amounts of
iron waste, and (b) the initiation of the rapidly exothermic
reaction is unpredictable. A different process, employing a
phosphine as reducing agent, is disclosed in WO 2007/115185. The
process of WO 2007/115185 is a workable process, upon which the
instant process is an improvement.
SUMMARY
The present disclosure provides an efficient and convenient method
for the conversion of an oxime to the corresponding enamide. The
method is appropriate for large-scale synthesis of enamides and,
from the enamides, synthesis of amides, amines, and their
derivatives.
In some embodiments, provided is a method for converting an oxime
into an enamide. The method comprises contacting an oxime with an
acyl donor and a phosphine in the presence of an iron reagent that
provides from 10 to 2000 ppm iron. The reaction is carried out
under conditions that convert the oxime to the enamide.
In some embodiments, provided is a method for converting a ketone
to an enamide. The method comprises (a) first reacting a ketone
with hydroxylamine to provide an oxime; and (b) second reacting the
oxime with an acyl donor and a phosphine in the presence of an iron
reagent that provides from 10 to 2000 ppm iron.
In some embodiments, provided is a method for converting a
prochiral ketone to an enantiomerically enriched chiral amide. The
method comprises: (a) first reacting a ketone with hydroxylamine to
provide an oxime; (b) second reacting the oxime with an acyl donor
and a phosphine in the presence of an iron reagent that provides
from 10 to 2000 ppm iron to provide an enamide; and (c) third
reducing the enamide with hydrogen in the presence of a chiral
catalyst to produce an enantiomerically enriched chiral amide.
In some embodiments, provided is a method for converting a
prochiral ketone to an enantiomerically enriched chiral amine. The
method comprises: (a) first reacting a ketone with hydroxylamine to
provide an oxime; (b) second reacting the oxime with an acyl donor
and a phosphine in the presence of an iron reagent that provides
from 10 to 2000 ppm iron to provide an enamide; (c) third reducing
the enamide with hydrogen in the presence of a chiral catalyst to
produce an enantiomerically enriched chiral amide; and (d) fourth
hydrolyzing the chiral amide to an enantiomerically enriched chiral
amine.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graph of reaction speed reflected as percent residual
oxime acetate versus time in hours in the presence of varying
amounts of iron.
FIG. 2 is a graph of reaction speed reflected as percent residual
oxime acetate versus time in hours in the presence of iron, zinc,
nickel, and copper.
FIG. 3 is a graph of reaction speed reflected as percent residual
oxime acetate versus time in hours in the presence of iron under
various temperature regimes
DETAILED DESCRIPTION
The description provided herein is made with the understanding that
the present disclosure is to be considered as an exemplification of
the claimed subject matter, and is not intended to limit the claims
to the specific embodiments. The headings used throughout this
disclosure are provided for convenience and are not to be construed
to limit the claims in any way. Embodiments under any heading may
be combined with embodiments under any other heading.
All published documents cited herein are hereby incorporated by
reference in their entirety.
Definitions
The description provided herein uses certain terms in the chemical
arts. Unless otherwise specified throughout the description herein,
terms retain their meaning as understood by one having ordinary
skill in the art.
As used herein, the terms "comprising" and "including" or
grammatical variants thereof are to be taken as specifying the
stated features, integers, steps or components, but do not preclude
the addition of one or more additional features, integers, steps,
components or groups thereof. This term encompasses the terms
"consisting of" and "consisting essentially of". The phrase
"consisting essentially of" or grammatical variants thereof, when
used herein, are to be taken as specifying the stated features,
integers, steps or components, but do not preclude the addition of
one or more additional features, integers, steps, components or
groups thereof, but only if the additional features, integers,
steps, components or groups thereof do not materially alter the
basic and novel characteristics of the claimed composition or
method.
As used herein, the singular forms "a", "an" and "the" are intended
to include the plural forms as well, unless the context clearly
indicates otherwise. It will be further understood that the terms
"comprise" (and any form of comprise, such as "comprises" and
"comprising"), "have" (and any form of have, such as "has" and
"having"), "include" (and any form of include, such as "includes"
and "including"), and "contain" (and any form contain, such as
"contains" and "containing") are open-ended linking verbs. As a
result, a method that "comprises", "has", "includes" or "contains"
one or more steps or elements possesses those one or more steps or
elements, but is not limited to possessing only those one or more
steps or elements.
Reference throughout the description to "one embodiment" or "an
embodiment" or "some embodiments" means that a particular feature,
structure or characteristic described in connection with the
embodiment is included in at least that embodiment. Use of "one
embodiment" or "an embodiment" or "some embodiments" throughout the
description are not necessarily referring to the same embodiments;
but particular features, structures, or characteristics may be
combined in any suitable manner in one or more embodiments.
As used herein, methods comprising numbered steps (e.g., first,
second, third, etc.) indicate that a first step occurs before a
second step and a second step occurs before a third step, but does
not necessarily preclude intermediate steps. For example, in "a
method of converting a ketone (K) to an enamide (E):
##STR00002## wherein the method comprises (a) first reacting a
ketone with hydroxylamine to provide an oxime; and (b) second
reacting the oxime with an acyl donor and a phosphorus reagent in
the presence of an iron reagent as described herein," step (a) must
occur before step (b) (e.g., step (a) precedes step (b)), but there
may be one or more intermediate steps between (a) and (b), such as
additional reactions or heating or washing or separating, etc.
Accordingly, "first," "second," "third," etc. are sequential steps
or events, but do not preclude intermediate steps between, for
example, ("first" and "second") or ("second" and "third")
steps.
A prefix such as "C.sub.x-C.sub.y" or "(C.sub.x-C.sub.y)" indicates
that the group following said prefix has from x toy carbon atoms.
For example, a "C.sub.1 to C.sub.20 hydrocarbon" indicates a
hydrocarbon having 1 to 20 carbon atoms.
As used herein, "hydrocarbon" refers to radical comprising carbon
atoms. In some embodiments, provided are C.sub.1-C.sub.20
hydrocarbons, which comprise 1 to 20 carbon atoms. Non-limiting
examples of hydrocarbons include alkyl, cycloalkyl, polycycloalkyl,
alkenyl, alkynyl, aryl and combinations thereof (e.g., arylalkyl).
Non-limiting examples of C.sub.1-C.sub.20 hydrocarbons include
methyl, ethyl, propyl, etc., cyclopropyl, phenyl, naphthyl, benzyl,
phenethyl, cyclohexylmethyl, adamantyl, camphoryl and
naphthylethyl.
As used herein, "hydrocarbyl" refers to any radical comprised of
hydrogen and carbon as the only elemental constituents.
As used herein, "aliphatic hydrocarbons" are hydrocarbons that are
not aromatic. An aliphatic hydrocarbon may be saturated or
unsaturated and cyclic, linear or branched. Non-limiting examples
of aliphatic hydrocarbons include isopropyl, 2-butenyl, 2-butynyl,
cyclopentyl, norbornyl, etc.
As used herein, "aromatic hydrocarbons" include phenyl, naphthyl,
anthracene, etc.
Unless otherwise specified, "alkyl" (or a related divalent radical
"alkylene") is intended to include linear or branched saturated
hydrocarbon structures and combinations thereof. In some
embodiments, an alkyl may have 1 to 20 carbon atoms (e.g.,
C.sub.1-C.sub.20 alkyl), or 1 to 10 carbon atoms (e.g.,
C.sub.1-C.sub.10 alkyl), or 1 to 6 carbon atoms (e.g.,
C.sub.1-C.sub.6 alkyl). Non-limiting examples of alkyl groups
include methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, t-butyl
and the like.
As used herein, "Cycloalkyl" is a cyclic hydrocarbon. In some
embodiments, a cycloalkyl may have 3 to 8 carbon atoms (e.g.,
C.sub.3-C.sub.8 cycloalkyl). Non-limiting examples of cycloalkyl
groups include cy-propyl, cy-butyl, cy-pentyl, norbornyl and the
like.
Unless otherwise specified, the term "carbocycle" is intended to
include ring systems (monocyclic) in which the ring atoms are all
carbon but of any oxidation state. Thus a carbocycle refers to both
non-aromatic and aromatic systems. A "carbopolycycle" refers to a
polycyclic (two or more rings) carbocycle. Non-limiting examples of
C.sub.3-C.sub.8 carbocycles include cyclopropane, benzene and
cyclohexene; and non-limiting examples of C.sub.8-C.sub.12
carbopolycycle include norbornane, decalin, indane and
naphthalene.
As used herein, the term "acyl donor" refers to a compound capable
of donating an acyl group under certain reaction conditions. In
some embodiments, acyl donors are anhydrides of carboxylic acids,
such as acetic anhydride. In some embodiments, the acyl donor is
acetic anhydride. Reference throughout this description to an "acyl
residue" refers to the hydrocarbon "R.sup.3" group from an acyl
donor. In some embodiments, the acyl residue (e.g., R.sup.3) is a
C.sub.1-C.sub.6 hydrocarbon. In some embodiments, the acyl residue
(e.g., R.sup.3) is methyl, pivaloyl or phenyl. In some embodiments,
the acyl residue (e.g., R.sup.3) is a C.sub.1-C.sub.6 alkyl. In
some embodiments, the acyl residue (e.g., R.sup.3) is methyl,
ethyl, or propyl.
As used herein, the term "phosphine" refers to a phosphorus reagent
having the following formula: P(Q).sub.3 wherein each Q is
independently selected from H, halogen, substituted or
unsubstituted alkyl and substituted or unsubstituted aryl. In some
embodiments, Q may be selected from C.sub.1-C.sub.6 alkyl and
phenyl. In some embodiments, phosphorus reagents include, but are
not limited to, diphenylphosphine (Ph.sub.2PH), triphenylphosphine
(Ph.sub.3P), tri-n-butylphosphine (n-Bu.sub.3P), triethylphosphine
(Et.sub.3P), tri-n-propylphosphine (n-Pr.sub.3P),
1,2-bisdiphenylphosphinoethane
(Ph.sub.2PCH.sub.2CH.sub.2PPh.sub.2), and chlorodiphenylphosphine
(Ph.sub.2PCl). In some embodiments, trialkyl phosphines (e.g.,
triethyl phosphine) are advantageous phosphorus reagents because a
phosphine oxide by-product is easily removed from the reaction
mixture at the end of the reaction. In some embodiments, the
phosphorus reagent is triethylphosphine (Et.sub.3P), In some
embodiments, the phosphine is tri n-butylphosphine (n-Bu.sub.3P),
triethyl phosphine (Et.sub.3P), diphenylphosphinoethane
(Ph.sub.2PCH.sub.2CH.sub.2PPh.sub.2), or triphenyl phosphine
(Ph.sub.3P). In some embodiments, the phosphine is
triethylphosphine (Et.sub.3P),
As used herein, the term "optionally substituted" may be used
interchangeably with "unsubstituted or substituted". The term
"substituted" refers to the replacement of one or more hydrogen
atoms in a specified group with a specified radical. For example,
"substituted hydrocarbyl" refers to a hydrocarbon in which one or
more hydrogen atoms are replaced with halogen, haloalkyl, acyl,
alkoxy, haloalkoxy, oxaalkyl, cyano, acetoxy, phenoxy, benzyloxy,
and the like. As used herein, and unless otherwise indicated, a
composition that is "substantially free" of a compound means that
the composition contains less than about 20% by weight, more
preferably less than about 10% by weight, even more preferably less
than about 5% by weight, and most preferably less than about 3% by
weight of the compound.
As used herein, the term "substantially optically pure" refers to a
non-racemic mixture of isomers in which one isomer constitutes at
least 80% of the mixture. In a preferred embodiment, the term
"substantially optically pure" means that the compound is made up
of at least 90% by weight of one isomer and 10% by weight or less
of its opposite isomer. In a more preferred embodiment, the term
means at least a 95:5 mixture.
As used herein, "diastereomeric excess" (abbreviated "de") for
diastereomer A refers to the amount of diastereomer A minus the
amount of diastereomer B divided by amount of diastereomer A plus
the amount of diastereomer B [(A-B)/(A+B)]. For example, when a
substance (such as a compound or crystal) is characterized as
having 90% de, that means that greater than 95% by weight of the
substance is one diastereomer and less than 5% by weight is any
other diastereomers.
The graphic representations of racemic, ambiscalemic and scalemic
or enantiomerically pure compounds used herein are taken from
Maehr, J. Chem. Ed., 62: 114-120 (1985): solid and broken wedges
are used to denote the absolute configuration of a chiral element;
wavy lines indicate disavowal of any stereochemical implication
which the bond it represents could generate; solid and broken bold
lines are geometric descriptors indicating the relative
configuration shown but not implying any absolute stereochemistry;
and wedge outlines and dotted or broken lines denote
enantiomerically pure compounds of indeterminate absolute
configuration.
Iron-Catalyzed Conversion
The methods described herein are not limited to practice on
specified enamides characterized by any particular structural
element or membership within any single structural class.
According, provided are methods of broad applicability across a
wide range of enamide structures.
A method for preparing a chiral amine from a ketone is illustrated
in the following scheme:
##STR00003## wherein K is a ketone, O is an oxime, E is an enamide,
C is a carboxamide, A is an amine, and R.sup.3 is the residue of an
acyl donor.
Oxime to Enamide
In some embodiments, provided is a method of converting an oxime
(O) to an enamide (E):
##STR00004##
In some embodiments, provided is a method of converting an oxime
(O) to an enamide (E):
##STR00005## wherein the method comprises contacting the oxime (O)
with an acyl donor and a phosphine in the presence of an iron
reagent that provides from 10 to 2000 ppm iron.
In another embodiment, provided is a method for converting an oxime
to an enamide, the method comprising contacting the oxime with an
acyl donor and a phosphine in the presence of an iron reagent that
provides from 10 to 2000 ppm iron under conditions that convert the
oxime to the enamide.
In some embodiments, provided is a method of converting an oxime
(O) to an enamide (E):
##STR00006## wherein the method comprises contacting the oxime (O)
with an acyl donor and a phosphine in the presence of an iron
reagent that provides from 10 to 1000 ppm iron.
In another embodiment, provided is a method for converting an oxime
to an enamide, the method comprising contacting the oxime with an
acyl donor and a phosphine in the presence of an iron reagent that
provides from 10 to 1000 ppm iron under conditions that convert the
oxime to the enamide.
In some embodiments, provided is a method of converting an oxime
(O) to an enamide (E):
##STR00007## wherein the method comprises contacting the oxime (O)
with an acyl donor and a phosphine in the presence of an iron
reagent that provides from 1000 to 2000 ppm iron.
In another embodiment, provided is a method for converting an oxime
to an enamide, the method comprising contacting the oxime with an
acyl donor and a phosphine in the presence of an iron reagent that
provides from 1000 to 2000 ppm iron under conditions that convert
the oxime to the enamide.
In some embodiments, provided is a method of converting an oxime
(O) to an enamide (E):
##STR00008##
wherein the method comprises contacting the oxime (O) with an acyl
donor and a phosphine in the presence of an iron reagent that
provides from 1500 to 2000 ppm iron.
In another embodiment, provided is a method for converting an oxime
to an enamide, the method comprising contacting the oxime with an
acyl donor and a phosphine in the presence of an iron reagent that
provides from 1500 to 2000 ppm iron under conditions that convert
the oxime to the enamide.
Ketone to Enamide
Provided is a method of converting a ketone (K) to an enamide (E).
An advantage of some embodiments described herein is the conversion
of the ketone (K) to the enamide (E) in a "single pot." For
example, while in some embodiments it may be possible to isolate
the oxime (O), it will not be necessary to obtain the enamide
(E).
Reacting the ketone (K) with a hydroxylamine may be done in the
presence of a base, such as sodium acetate, in a solvent. See,
e.g., Sandler and Karo, "ORGANIC FUNCTIONAL GROUP PREPARATIONS,"
Vol. 3, pp 372-381, Academic Press, New York, 1972. In some
embodiments, the ketone (K) may be an aliphatic ketone or arylalkyl
ketone (e.g., a naphthalenic ketone), as long as there is at least
one proton on an sp3 carbon adjacent the ketone.
In some embodiments, provided is a method of converting a ketone
(K) to an enamide (E):
##STR00009##
In some embodiments, provided is a method of converting a ketone
(K) to an enamide (E):
##STR00010## wherein the method comprises (a) first reacting a
ketone with hydroxylamine to provide an oxime; and (b) second
reacting the oxime with an acyl donor and a phosphine in the
presence of an iron reagent.
In another embodiment, provided is a method for converting a ketone
to an enamide, the method comprising: (a) first reacting the ketone
with hydroxylamine to provide an oxime; and (b) second reacting the
oxime with an acyl donor and a phosphine in the presence of an iron
reagent that provides from 10 to 2000 ppm iron.
In another embodiment, provided is a method for converting a ketone
to an enamide, the method comprising: (a) first reacting the ketone
with hydroxylamine to provide an oxime; and (b) second reacting the
oxime with an acyl donor and a phosphine in the presence of an iron
reagent that provides from 10 to 1000 ppm iron.
In another embodiment, provided is a method for converting a ketone
to an enamide, the method comprising: (a) first reacting the ketone
with hydroxylamine to provide an oxime; and (b) second reacting the
oxime with an acyl donor and a phosphine in the presence of an iron
reagent that provides from 1000 to 2000 ppm iron.
In another embodiment, provided is a method for converting a ketone
to an enamide, the method comprising: (a) first reacting the ketone
with hydroxylamine to provide an oxime; and (b) second reacting the
oxime with an acyl donor and a phosphine in the presence of an iron
reagent that provides from 1500 to 2000 ppm iron.
In some embodiments, provided is a method of converting a ketone
(K) to an enamide (E):
##STR00011## wherein the method comprises (a) first reacting a
ketone with hydroxylamine to provide an oxime; and (b) second
reacting the oxime with an acyl donor and a phosphine in the
presence of an iron reagent. In some embodiments, steps (a) and (b)
are carried out without isolation of the oxime.
In some embodiments, provided is a method for converting a
prochiral ketone (K) to an enantiomerically enriched chiral amide
(C):
##STR00012## wherein the method comprises: (a) first reacting the
prochiral ketone (K) with hydroxylamine to provide an oxime (O);
(b) second reacting the oxime (O) with an acyl donor and a
phosphine in the presence of an iron reagent that provides from 10
to 2000 ppm iron to provide an enamide (E); and (c) third reducing
the enamide (E) with hydrogen in the presence of a chiral catalyst
to produce an enantiomerically enriched chiral amide (C).
In some embodiments, provided is a method for converting a
prochiral ketone (K) to an enantiomerically enriched chiral amide
(C):
##STR00013## wherein the method comprises: (a) first reacting the
prochiral ketone (K) with hydroxylamine to provide an oxime (O);
(b) second reacting the oxime (O) with an acyl donor and a
phosphine in the presence of an iron reagent that provides from 10
to 1000 ppm iron to provide an enamide (E); and (c) third reducing
the enamide (E) with hydrogen in the presence of a chiral catalyst
to produce an enantiomerically enriched chiral amide (C).
In some embodiments, provided is a method for converting a
prochiral ketone (K) to an enantiomerically enriched chiral amide
(C):
##STR00014## wherein the method comprises: (a) first reacting the
prochiral ketone (K) with hydroxylamine to provide an oxime (O);
(b) second reacting the oxime (O) with an acyl donor and a
phosphine in the presence of an iron reagent that provides from
1000 to 2000 ppm iron to provide an enamide (E); and (c) third
reducing the enamide (E) with hydrogen in the presence of a chiral
catalyst to produce an enantiomerically enriched chiral amide
(C).
In some embodiments, provided is a method for converting a
prochiral ketone (K) to an enantiomerically enriched chiral amide
(C):
##STR00015## wherein the method comprises: (a) first reacting the
prochiral ketone (K) with hydroxylamine to provide an oxime (O);
(b) second reacting the oxime (O) with an acyl donor and a
phosphine in the presence of an iron reagent that provides from
1500 to 2000 ppm iron to provide an enamide (E); and (c) third
reducing the enamide (E) with hydrogen in the presence of a chiral
catalyst to produce an enantiomerically enriched chiral amide
(C).
In some embodiments, provided is a method for converting a
prochiral ketone (K) to an enantiomerically enriched chiral amine
(A):
##STR00016## wherein the method comprises: (a) first reacting the
prochiral ketone (K) with hydroxylamine to provide an oxime (O);
(b) second reacting the oxime (O) with an acyl donor and a
phosphine in the presence of an iron reagent that provides from 10
to 2000 ppm iron to provide an enamide (E); (c) third reducing the
enamide (E) with hydrogen in the presence of a chiral catalyst to
produce an enantiomerically enriched chiral amide (C); and (d)
fourth hydrolyzing the enantiomerically enriched chiral amide (C)
to an enantiomerically enriched chiral amine (A).
In some embodiments, provided is a method for converting a
prochiral ketone (K) to an enantiomerically enriched chiral amine
(A):
##STR00017## wherein the method comprises: (a) first reacting the
prochiral ketone (K) with hydroxylamine to provide an oxime (O);
(b) second reacting the oxime (O) with an acyl donor and a
phosphine in the presence of an iron reagent that provides from 10
to 1000 ppm iron to provide an enamide (E); (c) third reducing the
enamide (E) with hydrogen in the presence of a chiral catalyst to
produce an enantiomerically enriched chiral amide (C); and (d)
fourth hydrolyzing the enantiomerically enriched chiral amide (C)
to an enantiomerically enriched chiral amine (A).
In some embodiments, provided is a method for converting a
prochiral ketone (K) to an enantiomerically enriched chiral amine
(A):
##STR00018## wherein the method comprises: (a) first reacting the
prochiral ketone (K) with hydroxylamine to provide an oxime (O);
(b) second reacting the oxime (O) with an acyl donor and a
phosphine in the presence of an iron reagent that provides from
1000 to 2000 ppm iron to provide an enamide (E); (c) third reducing
the enamide (E) with hydrogen in the presence of a chiral catalyst
to produce an enantiomerically enriched chiral amide (C); and (d)
fourth hydrolyzing the enantiomerically enriched chiral amide (C)
to an enantiomerically enriched chiral amine (A).
In some embodiments, provided is a method for converting a
prochiral ketone (K) to an enantiomerically enriched chiral amine
(A):
##STR00019## wherein the method comprises: (a) first reacting the
prochiral ketone (K) with hydroxylamine to provide an oxime (O);
(b) second reacting the oxime (O) with an acyl donor and a
phosphine in the presence of an iron reagent that provides from
1500 to 2000 ppm iron to provide an enamide (E); (c) third reducing
the enamide (E) with hydrogen in the presence of a chiral catalyst
to produce an enantiomerically enriched chiral amide (C); and (d)
fourth hydrolyzing the enantiomerically enriched chiral amide (C)
to an enantiomerically enriched chiral amine (A).
In some embodiments, provided is a process for preparing amine
(A)
##STR00020## according to the following general scheme:
##STR00021## wherein the process comprises reacting the oxime (O)
with an acyl donor and a phosphine in the presence of an iron
reagent that provides from 10 to 2000 ppm iron to provide an
enamide (E). In some embodiments, the iron reagent provides from 10
to 1000 ppm iron. In some embodiments, the iron reagent provides
from 1000 to 2000 ppm iron. In some embodiments, the iron reagent
provides from 1500 to 2000 ppm iron.
In some embodiments, provided is a process for preparing a compound
(6)
##STR00022## according to the following general scheme:
##STR00023## wherein the process comprises reacting the oxime (2)
with an acyl donor and a phosphine in the presence of an iron
reagent that provides from 10 to 2000 ppm iron to provide an
enamide (4). In some embodiments, the iron reagent provides from 10
to 1000 ppm iron. In some embodiments, the iron reagent provides
from 1000 to 2000 ppm iron. In some embodiments, the iron reagent
provides from 1500 to 2000 ppm iron.
In some embodiments, the enantiomerically enriched chiral amine (C)
is substantially optically pure.
In some embodiments, the oxime is an aliphatic ketone oxime. In
some embodiments, the oxime is a tetralone oxime. In some
embodiments, the oxime is
##STR00024##
In some embodiments, the amine is
##STR00025##
In some embodiments, provided is a method of accelerating the
conversion of an oxime to an enamide comprising a method described
herein. In some embodiments, provided is a method of accelerating
the conversion of a ketone to an enamide comprising a method
described herein.
In some embodiments, provided herein is a method for converting an
oxime to an enamide, the process comprising contacting the oxime
with an acyl donor and a phosphine in the presence of an iron
reagent that provides from 10 to 2000 ppm iron under conditions
that convert the oxime to the enamide.
In some embodiments, provided herein is a method for converting a
ketone to an enamide, the process comprising the sequential steps
of: (a) reacting the ketone with hydroxylamine to provide an oxime;
and (b) reacting the oxime with an acyl donor and a phosphine in
the presence of an iron reagent that provides from 10 to 2000 ppm
iron.
In some embodiments, provided herein is a method for converting a
prochiral ketone to an enantiomerically enriched chiral amide, the
process comprising: (a) reacting the ketone with hydroxylamine to
provide an oxime; (b) reacting the oxime with an acyl donor and a
phosphine in the presence of an iron reagent that provides from 10
to 2000 ppm iron to provide an enamide; and (c) reducing the
enamide with hydrogen in the presence of a chiral catalyst to
produce an enantiomerically enriched chiral amide.
In some embodiments, provided herein is a method for converting a
prochiral ketone to an enantiomerically enriched chiral amine, the
process comprising: (a) reacting the ketone with hydroxylamine to
provide an oxime; (b) reacting the oxime with an acyl donor and a
phosphine in the presence of an iron reagent that provides from 10
to 2000 ppm iron to provide an enamide; (c) reducing the enamide
with hydrogen in the presence of a chiral catalyst to produce an
enantiomerically enriched chiral amide; and (d) hydrolyzing the
chiral amide to an enantiomerically enriched chiral amine.
In some embodiments, provided is the method as described in any one
or more of the preceding four paragraphs wherein the acyl donor is
acetic anhydride.
In some embodiments, provided is the method as described in any one
or more of the preceding five paragraphs wherein the phosphine is
chosen from tri n-butylphosphine, triethyl phosphine,
diphenylphosphinoethane and triphenyl phosphine.
In some embodiments, provided is the method as described in any one
or more of the preceding six paragraphs wherein the phosphine is
triethyl phosphine.
In some embodiments, provided is the method as described in any one
or more of the preceding seven paragraphs wherein the iron reagent
is chosen from elemental iron and Fe(II) salts and Fe(III) salts
wherein the counter ion is halide or alkanoate.
In some embodiments, provided is the method as described in any one
or more of the preceding eight paragraphs wherein the iron reagent
is chosen from FeCl.sub.2 and Fe(OAc).sub.2.
In some embodiments, provided is the method as described in any one
or more of the preceding nine paragraphs wherein the iron reagent
provides from 10 to 2000 ppm iron.
In some embodiments, provided is the method as described in any one
or more of the preceding ten paragraphs wherein the iron reagent
provides from 10 to 1900 ppm iron.
In some embodiments, provided is the method as described in any one
or more of the preceding eleven paragraphs wherein the iron reagent
provides from 10 to 1800 ppm iron.
The invention further relates to a process as described in any one
or more of the preceding tweleve paragraphs wherein the iron
reagent provides from 25 to 1800 ppm iron.
In some embodiments, provided is the method as described in any one
or more of the preceding thirteen paragraphs wherein the iron
reagent provides from 50 to 1800 ppm iron.
In some embodiments, provided is the method as described in any one
or more of the preceding fourteen paragraphs wherein the iron
reagent provides from 100 to 1800 ppm iron.
In some embodiments, provided is the method as described in any one
or more of the preceding fifteen paragraphs wherein the iron
reagent provides from 200 to 1700 ppm iron.
The invention further relates to a process as described in any one
or more of the first twelve of the preceding sixteen paragraphs
wherein the iron reagent provides from 10 to 100 ppm iron.
In some embodiments, provided is the method as described in any one
or more of the first twelve of the preceding seventeen paragraphs
wherein the iron reagent provides from 10 to 50 ppm iron.
In some embodiments, provided is the method as described in any one
or more of the first twelve of the preceding eighteen paragraphs
wherein the iron reagent provides from 25 to 100 ppm iron.
In some embodiments, provided is the method as described in any one
or more of the first twelve of the preceding nineteen paragraphs
wherein the iron reagent provides from 50 to 200 ppm iron.
In some embodiments, provided is the method as described in any one
or more of the preceding twenty paragraphs wherein the process is
carried out in a solvent at a temperature between 80.degree. C. and
150.degree. C.
In some embodiments, provided is the method as described in any one
or more of the preceding twenty-one paragraphs wherein the solvent
is toluene.
In some embodiments, provided is the method as described in any one
or more of the preceding twenty-two paragraphs wherein the oxime is
an aliphatic ketone oxime.
In some embodiments, provided is the method as described in any one
or more of the preceding twenty-three paragraphs wherein the oxime
is a tetralone oxime.
In some embodiments, provided is the method as described in any one
or more of the preceding twenty-three paragraphs wherein steps (a)
and (b) are carried out without isolation of the oxime.
In some embodiments, provided is the method as described in any one
or more of the preceding twenty-four paragraphs wherein the acyl
donor is acetic anhydride, the phosphine is triethyl phosphine and
the iron reagent is chosen from FeCl.sub.2 and Fe(OAc).sub.2.
In some embodiments, provided is the method as described in any one
or more of the preceding twenty-six paragraphs wherein the oxime
is
##STR00026##
In some embodiments, provided is the method as described in any one
or more of the first twenty-two of the preceding twenty-five
paragraphs wherein the amine is
##STR00027##
In one embodiment of these processes relating to the foregoing
oxime and amine, the acyl donor is acetic anhydride, the phosphine
is triethyl phosphine, and the iron reagent is FeCl.sub.2 and/or
Fe(OAc).sub.2.
Exemplary reagents and reaction conditions for the conversion of an
enamide to an amide are set forth in PCT application WO
2007/115185, which is hereby incorporated by reference in its
entirety.
Catalysts
In some embodiments, the methods described herein for reducing an
enamide (E) to an amide (e.g., enantiomerically enriched chiral
amide (C)) includes contacting the enamide (E) with a hydrogenation
catalyst and hydrogen or a hydrogen transfer reagent under
conditions appropriate to hydrogenate the carbon-carbon double bond
of the enamide (E). In some embodiments, the enamide substrate is
chiral or prochiral and the reduction is performed in a
stereoselective manner. In some embodiments, the catalyst is a
chiral catalyst. In some embodiments, the chiral catalyst is a
transition metal catalyst. In some embodiments, the catalyst is a
transition metal catalyst.
Chiral transition metal complex catalysts may be used in catalytic
asymmetric hydrogenation reactions. For example, transition metal
complexes of ruthenium, iridium, rhodium, palladium, nickel or the
like, which contain optically active phosphines as ligands, have
performed as catalysts for asymmetric synthetic reactions, and/or
are used in industrial application. See, e.g., ASYMMETRIC CATALYSIS
IN ORGANIC SYNTHESIS, Ed., R. Noyori, Wiley & Sons (1994); and
G. Franck), et al., Angewandte Chemie. Int. Ed., 39: 1428-1430
(2000). In some embodiments, the metal in the catalyst is rhodium
(Rh), ruthenium (Ru) or iridium (Ir).
In some embodiments, the hydrogenation catalyst is a chiral complex
of a transition metal with a chiral phosphine ligand, including
monodentate and bidentate ligands. For example, bidentate ligands
include 1,2-bis(2,5-dimethylphospholano)ethane (MeBPE),
P,P-1,2-phenylenebis{(2,5-endo-dimethyl)-7-phosphabicyclo[2.2.1]heptane}
(MePennPhos), 5,6-bis(diphenylphosphino) bicyclo[2.2.1]hept-2-ene
(NorPhos) and 3,4-bis(diphenylphosphino) N-benzyl pyrrolidine
(commercially available as catASium.RTM. D).
##STR00028##
In some embodiments, the chiral catalyst is
(R,S,R,S)-MePennPhos(COD)RhBF.sub.4, (R,R)-MeBPE(COD)RhBF.sub.4,
(R,R)-NorPhos(COD)RhBF.sub.4 (Brunner et al., Angewandte Chemie
91(8): 655-6 (1979)), or (R,R)-catASium.RTM. D(COD)RhBF.sub.4
(Nagel et al., Chemische Berichte 119(11): 3326-43 (1986)).
A catalyst may be present in the reaction mixture in any useful
amount. In some embodiments, the catalyst is present in an amount
of from about 0.005 mol % to about 1 mol %. In some embodiments the
catalyst is present in an amount of from about 0.01 mol % to about
0.5 mol %. In some embodiments the catalyst is present in an amount
of from about 0.02 mol % to about 0.2 mol %.
Deacylating Reagents
Some methods of deacylating amides to the corresponding amines are
known in the art. In some embodiments, a deacylating reagent is
used to hydrolyze the amide to the corresponding amine. In some
embodiments, the deacylating reagent is an enzyme. Exemplary
enzymes of use in this process include those of the class EC 3.5.1
(e.g., amidase, aminoacylase), and EC 3.4.19.
In another embodiment, the deacylating reagent is an acid or a
base. The acid or base can be either inorganic or organic. Mixtures
of acids or mixtures of bases are useful as well. When the
deacylating reagent is an acid, it is generally preferred that the
acid is selected so that the acid hydrolysis produces a product
that is a salt form of the amine. In some embodiments, the acid is
hydrochloric acid (HCl).
Other deacylating conditions of use in the present invention
include, but are not limited to, methanesulfonic acid/HBr in
alcoholic solvents, triphenylphosphite/halogen (e.g., bromine,
chlorine) complex and a di-t-butyl dicarbonate/lithium hydroxide
sequence.
In some cases, the amide is deacylated by treatment with an
activating agent, e.g., trifluoromethanesulfonic anhydride,
phosgene, and preferably, oxalyl chloride/pyridine. The reaction is
quenched with an alcohol, often a glycol, such as propylene
glycol.
Phosphorus Reagents
A phosphorus reagent (e.g., a phosphine) may be incorporated into
the reaction mixture in substantially any useful amount. In some
embodiments, reactions utilize from about 0.5 equivalents to about
5 equivalents of the phosphorus reagent with respect to the
carbonyl-containing substrate. In some embodiments, reactions
utilize from about 1 equivalent to about 3 equivalents of the
phosphorus reagent with respect to the carbonyl-containing
substrate. In some embodiments, reactions utilize from about 1.1
equivalents to about 2 equivalents of the phosphorus reagent with
respect to the carbonyl-containing substrate.
Iron Reagents
The iron reagent may be elemental iron, or it may be an Fe(II) or
Fe(III) salt in which the counter ion is halide or alkanoate.
Ferrous chloride, ferrous acetate, ferric chloride, and ferric
acetate have the advantage of being convenient to handle and may be
added to the reaction mixture as a solution or suspension. In some
embodiments, the iron reagent should provide from 10 to 1000 ppm
iron, based on weight of iron in the iron source to weight of the
ketone. In some embodiments, the iron reagent should provide from
10 to 2000 ppm iron, based on weight of iron in the iron source to
weight of the ketone. In some embodiments, the iron reagent should
provide from 1000 to 2000 ppm iron, based on weight of iron in the
iron source to weight of the ketone. In some embodiments, the iron
reagent should provide from 1500 to 2000 ppm iron, based on weight
of iron in the iron source to weight of the ketone. So for example,
for a 100 g ketone reaction, 50 ppm equates to 18 mg of
FeCl.sub.2-4H.sub.2O (ferrous chloride tetrahydrate being 28% iron
by weight). Possible ranges, in ppm, for the iron reagent are
10-50, 10-100, 10-200, 10-250, 10-400, 10-500, 10-700, 10-800,
10-1000, 25-50, 25-100, 25-200, 25-250, 25-400, 25-500, 25-700,
25-800, 25-1000, 40-100, 40-200, 40-250, 40-400, 40-500, 40-700,
40-800, 40-1000, 50-100, 50-200, 50-250, 50-400, 50-500, 50-700,
50-800, and 50-1000. Possible ranges, in ppm, for the iron reagent
are 10-2000, 50-2000, 100-2000, 150-2000, 200-2000, 250-2000,
300-2000, 350-2000, 400-2000, 450-2000, 500-2000, 550-2000,
600-2000, 650-2000, 700-2000, 750-2000, 800-2000, 850-2000,
900-2000, 950-2000, 1000-2000, 1050-2000, 1100-2000, 1150-2000,
1200-2000, 1250-2000, 1300-2000, 1350-2000, 1400-2000, 1450-2000,
1500-2000, 1550-2000, 1600-2000, 1650-2000, 1700-2000, 1750-2000,
1800-2000, 1850-2000, 1900-2000, and 1950-2000.
In some embodiments, the iron reagent is elemental iron, an Fe(II)
salt, or an Fe(III) salt wherein the counter ion is halide or
alkanoate. In some embodiments, the iron reagent is FeCl.sub.2 or
Fe(OAc).sub.2. In some embodiments, the iron reagent is FeCl.sub.2
and Fe(OAc).sub.2. In some embodiments, the iron reagent is
FeCl.sub.2. In some embodiments, the iron reagent is
Fe(OAc).sub.2.
In some embodiments, the iron reagent provides from 10 to 2000 ppm
iron. In some embodiments, the iron reagent provides from 10 to
1000 ppm iron. In some embodiments, the iron reagent provides from
1000 to 2000 ppm iron. In some embodiments, the iron reagent
provides from 1500 to 2000 ppm iron. In some embodiments, the iron
reagent provides from 10 to 100 ppm iron. In some embodiments, the
iron reagent provides from 10 to 50 ppm iron. In some embodiments,
the iron reagent provides from 25 to 100 ppm iron. In some
embodiments, the iron reagent provides from 50 to 200 ppm iron.
The methods disclosed herein may, under normal circumstances in
which the oxime contains less than 10 ppm of iron, involve a step
of adding a solution or suspension of the appropriate iron reagent
to the oxime, either before, after, or concurrent with, the
addition of one or both of the other components (acyl donor and
phosphine).
Methods described herein may typically be carried out in a solvent
at a temperature between about 80.degree. C. and about 150.degree.
C. A process described herein below about 80.degree. C. may still
work, and there may be occasion when the stability of the oxime
will dictate a lower temperature, but on most occasions, time will
be saved by running the reaction above 80.degree. C.
Correspondingly, a reaction could be run at temperatures above
150.degree. C., but many reactants and products are not stable at
such high temperatures and thus the purity of the product may be
compromised above 150.degree. C. To achieve temperatures in the
desired range, the preferred solvents will be inert solvents,
typically aprotic solvents, having a boiling point between
80.degree. C. and 150.degree. C. A solvent that fits these criteria
is toluene. Others include chlorobenzene, xylene, acetonitrile and
dioxane.
In some embodiments, a method described herein is carried out in a
solvent at a temperature between about 80.degree. C. and about
150.degree. C. In some embodiments, a method described herein is
carried out in a solvent at a temperature between 80.degree. C. and
150.degree. C.
In some embodiments, the solvent is toluene, chlorobenzene, xylene,
acetonitrile or dioxane. In some embodiments, the solvent is
toluene. In some embodiments, the solvent is chlorobenzene. In some
embodiments, the solvent is xylene. In some embodiments, the
solvent is acetonitrile. In some embodiments, the solvent is
dioxane.
In some embodiments, the acyl donor is acetic anhydride, the
phosphine is triethyl phosphine and the iron reagent is FeCl.sub.2
or Fe(OAc).sub.2. In some embodiments, the acyl donor is acetic
anhydride, the phosphine is triethyl phosphine and the iron reagent
is FeCl.sub.2 and Fe(OAc).sub.2. In some embodiments, the acyl
donor is acetic anhydride, the phosphine is triethyl phosphine and
the iron reagent is FeCl.sub.2, In some embodiments, the acyl donor
is acetic anhydride, the phosphine is triethyl phosphine and the
iron reagent is Fe(OAc).sub.2.
In some embodiments, provided are methods for the conversion of
oximes to the corresponding enamides in which only catalytic
quantities of metal are required. In some embodiments, the enamides
are formed in high yields and purities. The process may be amenable
to large-scale production. Exemplary conditions are set forth below
for oximes of formula
##STR00029## wherein R.sup.1, R.sup.2, and R.sup.3 are hydrocarbyl
residues or substituted hydrocarbyl residues.
In some embodiments, an optically pure tetralone (1) is converted
into the corresponding oxime (2) and then to the enamide (4):
##STR00030## wherein optically pure tetralone (1) is treated with
hydroxylamine hydrochloride, and sodium acetate in methanol,
toluene or a mixture of the two, to afford the oxime (2). The oxime
(2) can either be isolated or carried forward as a solution in a
suitable solvent to the next step. Acylation of the oxime (2)
(e.g., using an acyl donor such as acetic anhydride) affords the
0-acetyloxime intermediate (3). It is thought that one electron
reduction of the O-acetyloxime gives the imine radical, which then
undergoes a second one-electron reduction to generate the iminium
anion. Next, acylation of the iminium anion with a second
equivalent of acetic anhydride, followed by tautomerization leads
to the enamide (4).
In some embodiments, the enamide (4) is converted to an amide
(5):
##STR00031##
When using rhodium catalyst systems based on chiral bidentate
ligands, such as those derived from 1,2-bis(phospholano)ethane
(BPE) ligands, P,P-1,2-phenylenebis(7-phosphabicyclo[2.2.1]heptane)
(PennPhos) ligands, 5,6-bis(phosphino)bicyclo[2.2.1]hept-2-ene
(NorPhos) ligands, or 3,4-bis(phosphino) pyrrolidine (commercially
available as catASium.RTM. D) ligands, the diastereomeric purity of
the trans amide derived from the corresponding enamide is high. In
some embodiments, the enamide (4) is hydrogenated at about 4 to
about 6 bar hydrogen pressure using about 0.03 to about 0.05 mol %
of a Rh-Me-BPE catalyst in isopropanol, to give the trans N-acetyl
amide (5) in greater than 95% de.
In some embodiments, the enamide (4) is hydrogenated at about 4 to
about 5 bar hydrogen pressure, using about 0.2 to about 0.5 mol %
of a Rh-PennPhos catalyst in isopropanol, to give the trans
N-acetyl amide (5) in at least 95% de.
In some embodiments the enamide (4) is hydrogenated at about 5 to
about 8 bar hydrogen pressure, using about 0.01 to about 0.05 mol %
of (R,R)NorPhos(COD)RhBF.sub.4 catalyst in isopropanol to give the
trans N-acetyl amide (5) in at least 95% de.
The stereoisomerically enriched amide may be purified, or further
enriched, by methods known in the art, e.g., chiral chromatography,
selective crystallization and the like. Amide (5) has been purified
by selective crystallization to about 99% de.
N-Deacylation of (5) affords trans
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine (6),
which although depicted below as the free base, is usually
recovered as a salt of the acid in which the hydrolysis was carried
out.
##STR00032## The method is particularly useful for the large-scale
synthesis of bioactive species, such as sertraline and sertraline
analogs, and the trans isomers of sertraline, norsertraline and
analogs thereof. Sertraline, (1S,4S)-cis
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine,
is approved for the treatment of depression by the United States
Food and Drug Administration, and is available under the trade name
ZOLOFT.RTM. (Pfizer Inc., NY, N.Y., USA). (1R,4S)-trans
4-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine,
colloquially known as transnorsertraline or dasotraline, is
currently in clinical trials for ADHD. Thus, a commercial scale
process that converts commercially available achiral ketones to
their corresponding chiral amines with high enantioselectivity is
of great value.
Compounds and Intermediates
(S)--N-acetyl-N-(4-(3,4-dichlorophenyl)-3,4-dihydronaphthalen-1-yl)acetam-
ide. In some embodiments, provided is the compound:
##STR00033##
Examples
The following examples are for the purpose of illustrating
embodiments, and are not to be construed as limiting the scope of
this disclosure in any way. The reactants used in the examples
below may be obtained either as described herein, or if not
described herein, are themselves either commercially available or
may be prepared from commercially available materials by methods
known in the art.
A. Synthesis of
(1R,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-amine
hydrochloride (6)
Synthesis of Oxime (2)
A suspension formed from a mixture of (S)-tetralone (1) (56.0 g,
0.192 mol), hydroxylamine hydrochloride (14.7 g, 0.212 mol), and
sodium acetate (17.4 g, 0.212 mol) in methanol (168 mL) was heated
to reflux for 1 to 5 hours under a N.sub.2 atmosphere. The progress
of the reaction was monitored by HPLC. After the reaction was
complete, the reaction mixture was concentrated in vacuo. The
residue was diluted with toluene (400 mL) and 200 mL water. The
organic layer was separated and washed with an additional 200 mL
water. The organic layer was concentrated and dried to give crude
solid oxime (2) (58.9 g, 100%), m. p. 117-120.degree. C. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. (ppm) 9.17 (br, 1H, OH), 7.98 (m,
1H), 7.36 (d, 1H, J=8.0 Hz), 7.29 (m, 2H), 7.20 (d, 1H, J=2.4 Hz),
6.91 (m, 2H), 4.11 (dd, 1H, J=7.2 Hz, 4.4 Hz), 2.82 (m, 2H), 2.21
(m, 1H), 2.08 (m, 1H). .sup.13C NMR (100 MHz, CDCl.sub.3) .delta.
154.94, 144.41, 140.40, 132.83, 130.92, 130.82, 130.68, 130.64,
129.98, 129.38, 128.12, 127.64, 124.48, 44.52, 29.51, 21.27.
Synthesis of Enamide (4)
(N--((S)-4-(3,4-dichlorophenyl)-3,4-dihydronaphthalen-1-yl)acetamide)
##STR00034##
The enamide (4) may be made from ketone (1) without isolation of
the above intermediate oxime (2) by acylating in situ to afford the
O-acetyloxime intermediate (3), which undergoes reductive acylation
to provide a mixture of the enamide (4) and a diacylated enamine
(4A). The reaction is carried out in either toluene or o-xylene at
reflux. The mixture of (4) and (4A) may then treated with an
aqueous solution of base such as sodium hydroxide or sodium
carbonate, with or without a phase transfer catalyst (e.g.
tetrabutylammonium hydrogen sulfate/hydroxide), to convert the
diacylated enamine (4A) to the desired enamide (4).
To a 1-liter, 3-neck round bottom flask equipped with an overhead
stirrer, temperature probe and a reflux condenser was added 50.0
grams (172 mmol) of ketone (1), 14.3 g (206 mmol) of hydroxylamine
HCl, 16.9 g (206 mmol) of sodium acetate, 7 g of methanol and 175 g
of toluene. The mixture was heated to reflux (.about.80.degree. C.)
for 2 h. After 2 h, the mixture was cooled to 20-25.degree. C., and
100 g of DI water was added. The solution was transferred to a 500
mL separatory funnel. The lower aqueous layer was drained and
discarded. The organic layer was washed with 100 g of DI water. The
lower aqueous layer was drained and discarded. The resulting
organic layer was transferred to a 500 mL, 3-neck round bottom
flask equipped with an overhead stirrer, temperature probe and a
reflux condenser fitted with a 20 mL Dean-Stark receiver with a
PTFE stopcock. Next, 0.5 mL of a 1.78 wt % aq. FeCl.sub.2 solution
was added (prepared by dissolving 454 mg of FeCl.sub.2.4H.sub.2O in
25.4 g of DI water). The solution was heated to reflux and stirred
for 1 h to remove water. The solution was then distilled and 112 g
of distillate was collected. The solution was then cooled to
60-65.degree. C. and 19.2 g (188 mmol) of acetic anhydride and 22.3
g (189 mmol) of triethylphosphine were added. Caution:
Triethylphosphine is pyrophoric and should be handled with extreme
care. The Dean-Stark receiver was removed at this point. The
solution was slowly heated to reflux and stirred for 2 h. After 2
h, the solution was cooled to 20-25.degree. C., and 106 g of 6N
NaOH and 1.7 g of tetrabutylammonium hydroxide (1M solution in
MeOH) was added. The biphasic mixture was stirred at 25-30.degree.
C. for 1 h with vigorous mixing. The solution was then transferred
to a 500 mL separatory funnel. The lower aqueous layer was drained
and discarded. The organic layer was transferred to a 1-liter,
3-neck jacketed round bottom flask (with bottom drain-valve)
equipped with an overhead stirrer, temperature probe and a reflux
condenser. To the solution was added 100 g of toluene, followed by
150 g of 1 wt % aq. acetic acid. The slurry was heated to
65-70.degree. C. to achieve dissolution of the product. The lower
aqueous layer was drained and discarded. The organic layer was
washed with DI water (3.times.100 g) at 65-70.degree. C. then
transferred to 1-liter, 3-neck round bottom flask equipped with an
overhead stirrer, temperature probe and a reflux condenser fitted
with a 20 mL Dean-Stark receiver with a PTFE stopcock. Next, 55 g
of toluene was added. The solution was heated to reflux and stirred
for 2 h to remove water. After 2 h, the solution was then distilled
and 57 g of distillate was collected. The solution was cooled to
80.degree. C. and was polish-filtered through a 150 mL filter
funnel (pre-coated with 10 g of Celite.TM. 545 filter aid) into a
clean 1-liter, 3-neck round bottom flask equipped with an overhead
stirrer, temperature probe and a reflux condenser fitted with a 20
mL Dean-Stark receiver with a PTFE stopcock. The flask and filter
were rinsed with 64 g of toluene (.about.70.degree. C.). The
mixture was heated to reflux and the solution was distilled to a
volume of approx. 205 mL. A total of 149 g of distillate was
collected. The solution was cooled to 60.degree. C. at which point
the enamide (4) began to crystallize and a slurry formed. The
slurry was cooled to 50.degree. C. and 70 g of n-heptane was added
over 60 minutes. The slurry was cooled to 20-25.degree. C. and
filtered. The product was washed with 186 g of 28 wt % n-heptane in
toluene. The wet-cake was dried in a vacuum oven overnight at
45.degree. C. to yield 50.8 g (89% yield) of enamide (4) as a white
solid (>99% purity by HPLC).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. (ppm) 7.35 (d, 1H, J=8.4
Hz), 7.26 (m, 3H), 7.17 (m, 1H), 7.05 (dd, 1H, J=8.0, 1.6 Hz), 7.00
(br, 1H), 6.87 (m, 0.82H, 82% NH rotamer), 6.80 (br, 0.18H, 18% NH
rotamer), 6.31 (t, 0.82H, J=4.8 Hz, 82% H rotamer), 5.91 (br,
0.18H, 18% H rotamer), 4.12 (br, 0.18H, 18% H rotamer), 4.03 (t,
0.82H, J=8.0 Hz, 82% H rotamer), 2.72 (m, 1H), 2.61 (ddd, 1H,
J=16.8, 8.0, 4.8 Hz), 2.17 (s, 2.46H, 82% CH.sub.3 rotamer), 1.95
(s, 0.54H, 18% CH.sub.3 rotamer). 100 MHz .sup.13C NMR (CDCl.sub.3)
.delta. 169.3, 143.8, 137.7, 132.3, 131.8, 131.4, 130.5, 130.3,
130.2, 128.8, 128.1, 127.8, 127.2, 123.8, 122.5, 121.2, 117.5,
42.6, 30.3, 24.1.
Synthesis of (1R,4S)-acetamide (5)
(N-((1R,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)acet-
amide)
The enamide (4) (24 g, 72 mmol) was slurried in degassed
isopropanol (200 mL). The resulting slurry was transferred to the
appropriate reactor. Prior to the addition of the catalyst
solution, the content of the reactor was purged with nitrogen. A
solution of (R,R)-MeBPE(COD)RhBF.sub.4 catalyst (20.1 mg, 0.036
mmol, 0.05 mol %) in isopropanol (IPA) (100 mL) was added to the
reactor. The content was cooled to 0.degree. C. and purged with
nitrogen three times. The reactor was then purged with hydrogen and
pressurized to 90 psig. The reaction was aged with agitation at
0.degree. C. for 7.5 h and conversion was monitored by the hydrogen
uptake. The content was then warmed to RT and hydrogen was vented.
After purging with nitrogen, the contents were drained. The
reaction mixture was heated to 50.degree. C. and filtered through a
pad of Celite. The solution was concentrated to .about.50% volume
(150 mL) and diluted with toluene (5.9 g, 5 wt %). The suspension
was heated to 65.degree. C. and water (14.7 mL) was added dropwise
to form a cloudy solution. The slurry was slowly cooled to
-10.degree. C. and aged for 30 minutes. The solid was filtered and
washed with cold IPA (2.times.45 mL). The cake was dried under
vacuum at 45.degree. C. overnight to afford 20.0 g (83% yield) of
(1R,4S)-acetamide (5) (>99% de). .sup.1H NMR (CDCl.sub.3) 400
MHz .delta. 7.34 (dd, 2H, J=7.9, 2.4 Hz), 7.23 (t, 1H, J=7.5 Hz),
7.15 (m, 2H), 6.85 (dd, 1H, J=8.2, 2.0 Hz), 6.82 (d, 1H, J=7.7 Hz),
5.72 (d, 1H, J=8.4 Hz), 5.31 (dd, 1H, J=13.2, 8.1 Hz), 4.10 (dd,
1H, J=7.0, 5.9 Hz), 2.17 (m, 2H), 2.06 (s, 3H), 1.87 (m, 1H). 1.72
(m, 1H); .sup.13C NMR (CDCl.sub.3) 100 MHz .delta. 169.7, 146.9,
138.8, 137.7, 132.6, 130.8, 130.6, 130.5, 130.3, 128.4, 128.3,
127.9, 127.4, 47.9, 44.9, 30.5, 28.4, 23.8.
Synthesis of amine hydrochloride (6)
((1R,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-amine
hydrochloride)
A solution of (1R,4S)-acetamide (5) (9.0 g, 26.9 mmol), n-propanol
(45 mL) and 5M hydrochloric acid (45 mL) was refluxed for
approximately 48 h (90-93.degree. C.). During this time, the
reaction temperature was maintained at .gtoreq.90.degree. C. by
periodically collecting the distillate until the reaction
temperature was .gtoreq.92.degree. C. Additional n-propanol was
added periodically to maintain the solution at its original volume.
After the hydrolysis was complete, the solution was slowly cooled
to 0.degree. C., resulting in a slurry, which was aged for one hour
at 0.degree. C. The reaction mixture was filtered, and the cake was
washed with 1:1 methanol/water (20 mL), followed by t-butyl methyl
ether (20 mL). The wet-cake was dried under vacuum at 45 to
50.degree. C. to afford 7.0 g of the amine hydrochloride (6) (80%
yield). .sup.1H NMR (DMSO-d.sub.6) .delta. 1.81-1.93 (m, 2H),
2.12-2.21 (m, 1H), 2.28-2.36 (m, 1H), 4.28 (t, 1H, J=6.8), 4.59
(br.s, 1H), 6.84 (d, 1H, J=7.6), 7.05 (dd, 1H, J=8.4, 1.6), 7.25
(t, 1H, J=7.6), 7.32 (t, 1H, J=7.6), 7.37 (d, 1H, J=1.6), 7.56 (d,
1H, J=8.4), 7.76 (d, 1H, J=7.2), 8.80 (br.s, 3H); .sup.13C NMR
(DMSO-d.sub.6) 147.4, 138.9, 133.6, 131.0, 130.5, 130.4, 130.1,
129.0, 128.9, 128.4, 128.2, 126.8, 47.9, 43.1, 27.8, 25.2.
Synthesis of amine hydrochloride (6) via Asymmetric Hydrogenation
Catalyzed by (R,R)-Norphos(COD)Rh--BF.sub.4
A slurry of enamide (4) (60.4 g, 0.18 mol), in isopropanol (595.0
g) was purged of oxygen with vacuum/nitrogen cycles. The
homogeneous catalyst precursor (referred to as a "catalyst"),
(R,R)-Norphos(COD)Rh--BF.sub.4 was added as a solution in methanol
(34.6 mg, 0.025 mol %, 0.53 mL). After purging the system with
hydrogen several times, the vessel was filled with hydrogen at the
desired reaction pressure (approx 7 bar). The mixture was stirred
at 25.degree. C. and reaction progress was monitored by hydrogen
uptake. Once the reaction was judged to be complete (hydrogen
uptake and HPLC), the pressure was released and the system was
purged repeatedly with nitrogen. The light yellow slurry was
diluted with isopropanol (194.7 g), heated to dissolution
(65.degree. C.) and polish filtered. The mixture was heated to
reflux to dissolve all solids. The solution was slowly cooled to
60-65.degree. C. at which time the product crystallized. The
antisolvent, water (262 g), was added at about 60-65.degree. C.,
then the mixture was cooled to 0.degree. C. over two hours and held
at that temperature for aging. Filtration of the lightly colored
solid was followed by washing with cold isopropanol (2.times.61 g).
Drying of the off white solid under reduced pressure at
50-55.degree. C. provided the (1R,4S)-acetamide (5) in 99% de (56.6
g, 93% yield).
A solution of (1R,4S)-acetamide (5) in dry THF (212.7 g, 239.3 mL)
was treated with dry pyridine (8.7 g, 8.9 mL, 110 mmol). The
resulting clear, colorless solution was cooled to approximately
0.degree. C. Oxalyl chloride (12.9 g, 8.9 mL, 101.6 mmol) was added
dropwise to the stirred solution, with care to control the exotherm
and effervescence of CO and CO.sub.2. The addition of the
activating reagent was accompanied by the formation of a slurry.
The slurry was allowed to stir cold for a short period (approx. 15
min) prior to sampling for conversion assessment. Once the reaction
was complete, dry propylene glycol was added to the reaction,
resulting in a minor exotherm. The reaction was warmed to
25.degree. C., during which time the slurry changed in color and
consistency. HPLC analysis of a second sample showed completion
before the addition of 1-propanol (96.9 g, 120.5 mL). 6N HCl (128.0
g, 120.0 mL) was added. The mixture was heated to effect
dissolution and the resulting mixture was polish filtered. THF was
removed by atmospheric distillation. After concentration of the
mixture, it was slowly cooled to 3.degree. C. The resulting lightly
colored slurry was filtered to yield and off-white cake. The cake
was first washed with 17 wt % n-PrOH in deionized water (72.6 g, 75
mL total) and then with cold MtBE (55.5 g, 75 mL). The off-white
wet cake was dried under vacuum at 45-50.degree. C. The amine
hydrochloride (6) was recovered as an off-white to white solid
(24.8 g, 84.1% yield) with excellent purity (>99% purity by
HPLC). Alternatively, the cake may be washed with methanol in water
followed by methanol in methyl tert-butyl ether, and recrystallized
from methanol/methyl tert-butyl ether.
Large Batch Synthesis of Enamide (4)
A larger-scaled synthesis of enamide (4) was completed using a
process similar to the ones described herein. In this larger-scaled
synthesis, ketone (1) (100 kg) was charged to a reactor with
hydroxylamine hydrochloride (28.7 kg) and sodium acetate (33.8 kg)
followed by toluene (350 kg) and methanol (14 kg). The mixture was
heated to approximately 80.degree. C. and allowed to react until
the ketone (1) starting material was not more than 1.5% by HPLC.
The completed reaction mixture was extracted with DI water at
approximately 25.degree. C. The aqueous phase was separated and the
organic phase was washed with DI water to afford oxime (2).
Iron(II) chloride in DI water was added followed by toluene. The
volume of this solution was reduced by distillation.
Acetic anhydride (38.5 kg) was added to afford O-acetyloxime
intermediate (3). Triethylphosphine (44.6 kg) was charged and the
reaction mixture was slowly heated and allowed to react slightly
under reflux until the remaining O-acetyloxime intermediate (3) was
not more than 2.0% by HPLC.
The reaction mixture, comprising enamide (4) and diacylated enamine
(4A) was cooled to about 20-25.degree. C. and 6N NaOH was added.
Tetrabutylammonium hydroxide was added and the enamide (4)
by-product was hydrolyzed at about 25-30.degree. C. The biphasic
mixture was then allowed to phase separate and the aqueous phase
was discarded. Subsequently, the organic phase was washed with 1%
acetic acid aqueous solution until the pH was NMT 7.0. The aqueous
phase was removed and the organic phase was washed with water.
Toluene was added, the organic phase was concentrated and the warm
solution was polish filtered. The solution was cooled to initiate
crystallization. n-Heptane was added, the slurry was aged and
cooled to about 20.degree. C. The intermediate was filtered and
washed twice with a solution consisting of a mixture of n-heptane
and toluene. The intermediate was vacuum dried at not more than
about 45.degree. C. to yield enamide (4) (85% yield).
B. Synthesis of N-(1-cyclohexylideneethyl)acetamide
##STR00035##
A mixture of hydroxylamine hydrochloride (6.6 g, 95.0 mmol), sodium
acetate (7.8 g, 95.1 mmol), toluene (40 mL), methanol (1.4 mL) and
cyclohexyl methyl ketone (10 g, 79.2 mmol) was heated to reflux
(.about.90.degree. C.). After about 1 h, the reaction was cooled to
about room temperature and extracted with water (2.times.20 mL).
The toluene solvent was removed by rotary evaporation and high
vacuum to provide 10.1 grams (91% yield) of oxime: m.p.
63-64.degree. C. .sup.1H and .sup.13C NMR spectra were consistent
to published data (Moran, J.; Gorelsky, S. I.; Dimitrijevic, E;
Lebrun, M.; Bedard, A.; Seguin, C.; Beauchemin, A., M.; J. Am.
Chem. Soc., 130, 2008, 17893). The crude oxime was used directly in
the next reaction without further purification.
To a solution of 1-cyclohexylethanone oxime (5.0 g, 35.4 mmol) and
toluene (30 mL) at 20.degree. C. was added dropwise acetic
anhydride (4.0 g, 39.2 mmol). The solution was cooled to about room
temperature over about 20 minutes and 32 mg of FeCl.sub.2.4H.sub.2O
(1792 ppm iron) and triethylphosphine (4.6 g, 38.9 mmol) were
added. The reaction mixture was slowly heated and stirred overnight
at reflux (.about.115.degree. C.). Next, the reaction mixture was
cooled to about room temperature and 1 wt % aq. CuSO.sub.4 (50 mL)
and EtOAc (100 mL) were added. The two liquid layers were
separated. The organic phase was washed with sat. aq. NaCl (25 mL)
and dried over Na.sub.2SO.sub.4. The organic phase was filtered and
the solvent removed by rotary evaporation and high vacuum to
provide 6.7 g of a crude solid. The material was triturated with
hexanes (15 mL), filtered and washed with hexanes (5 mL) to afford
2.4 g (41% yield) of product: m.p. 85-86.degree. C. (dec); TLC:
R.sub.f=0.19 (hexanes:EtOAc, 3:2, phosphomolybdic acid stain and
heat).
.sup.1H NMR (400 MHz, CDCl.sub.3, 4:1 mixture of rotamers) 6=6.71
(bs, 0.8H), 6.46 (bs, 0.2H), 2.20-2.12 (m, 2.7H), 2.07-2.04 (m,
1.6H), 1.99 (s, 2.2H), 1.88 (s, 0.6H), 1.83 (s, 2.2H), 1.80 (s,
0.6H), 1.41-1.53 (m, 6H) ppm. .sup.13C NMR (100 MHz, CDCl.sub.3,
4:1 mixture of rotamers) 6=173.1 (minor), 169.0 (major), 137.6
(minor), 133.3 (major), 121.8 (minor), 121.1 (major), 30.2 (minor),
29.8 (major), 29.50 (minor), 29.47 (major), 27.44 (major), 27.35
(major), 27.2 (minor), 26.5 (major), 26.4 (minor), 23.4 (major),
19.7 (minor), 18.9 (minor), 17.0 (major) ppm; HRMS: calcd. for
C.sub.10H.sub.17NO [M+H].sup.+: 168.1383, found 168.1376.
C. Synthesis of N-(non-4-en-5-yl)acetamide
##STR00036##
A mixture of hydroxylamine hydrochloride (5.9 g, 84.9 mmol), sodium
acetate (6.9 g, 84.4 mmol), toluene (40 mL), methanol (1.4 mL) and
5-nonanone (10 g, 70.3 mmol) was heated to reflux
(.about.88.degree. C.). After about 1.5 h, the reaction was cooled
to about room temperature and extracted with water (2.times.20 mL).
The toluene solvent was removed by rotary evaporation and high
vacuum to provide 11.0 grams (100% yield) of oxime as a liquid.
.sup.1H and .sup.13C NMR spectra were consistent with published
data (Moran, J.; Pfeiffer, J. Y.; Gorelsky, S., I.; Beauchemin, A.,
M.; Org. Lett., 11, 2009, 1895). The crude oxime was used directly
in the next reaction without further purification.
To a solution of 5-nonanone oxime (5.0 g, 31.7 mmol) and toluene
(30 mL) at about 21.degree. C. was added dropwise acetic anhydride
(3.6 g, 35.0 mmol). The solution was cooled from about 34.degree.
C. to about room temperature over about 25 minutes and 29 mg of
FeCl.sub.2.4H.sub.2O (1624 ppm iron) and triethylphosphine (4.1 g,
35.0 mmol) were added. The solution was slowly heated and stirred
overnight at reflux (.about.115.degree. C.). Next, the solution was
cooled to about room temperature and 1 wt % aq. CuSO.sub.4 (50 mL)
and EtOAc (100 mL) were added. The two liquid layers were
separated. The organic phase was washed with sat. aq. NaCl (25 mL)
and dried over Na.sub.2SO.sub.4. The organic phase was filtered and
the solvent removed by rotary evaporation to afford a liquid. The
crude material was purified by flash column chromatography on
silica gel (hexanes:EtOAc, 4:1 to 7:3 gradient) to afford 3.6 g
(62% yield) of product; TLC: R.sub.f=0.15 (hexanes:EtOAc, 8:2,
phosphomolybdic acid stain and heat). By NMR the product appeared
to be about a 1:1.5 mixture of Z and E isomers. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta.=7.27/7.18 (bs, 1H), 5.63/4.96 (t, J=7.3
Hz, 1H), 2.19-2.11 (m, 2H), 1.95/1.91 (s, 3H), 1.95-1.82 (m, 2H),
1.34-1.17 (m, 6H), 0.83-0.77 (m, 6H) ppm. .sup.13C NMR (100 MHz,
CDCl.sub.3) .delta.=169.1, 168.7, 134.8, 134.6, 121.9, 118.3, 34.7,
30.2, 29.7, 29.4, 29.2, 24.1, 23.4, 23.2, 22.42, 22.39, 22.2,
13.95, 13.91, 13.84 ppm; HRMS: calcd. for C.sub.11H.sub.21NO
[M+H].sup.+: 184.1696; found 184.1689. The E and Z geometric
isomers may be separated by routine processes well known to those
of skill in the art and then carried separately to chiral amides
and amines.
The three examples, one with a linear dialkyl ketone, one with a
cyclic alkyl ketone and one with an arylalkyl ketone demonstrate
the generality of the reaction for ketones and their oximes in
which there is at least one proton on an sp3 carbon adjacent the
ketone.
D. Iron PPM Acceleration
To confirm that ppm levels of iron accelerate the reaction, four
well-controlled laboratory experiments studied the effect of dosing
a small amount of iron at the beginning of the enacetamide
reaction. The results are shown in FIG. 1. Adding 25, 38 and 50 ppm
of iron (as FeCl.sub.2) to the reaction along with acetic anhydride
and triethyl phosphine after completion of the (S)-oxime aqueous
work-up resulted in complete reaction in less than two hours. A
control experiment was performed using ketone (1) that had been
assayed by ICP-MS and contained less than 0.2 ppm Fe. The control
had not yet reached completion at 19 hours.
To ascertain whether iron might have fortuitously affected reaction
rates in earlier disclosed conversions of oximes to enamides,
different batches of tetralone from the supplier for the
experiments in PCT WO 2007/115185 were assayed by ICP-MS and found
to contain from 1.99 ppm to 9.78 ppm iron. Reactions with these
batches of tetralone were generally complete in about 6-16 hours;
the speed of reaction varied roughly as a function of the amount of
iron contaminant. One may surmise that the correlation between iron
levels and reaction speed in samples with low levels of iron was
not uniform because, at levels below 10 ppm, one has not reached a
threshold for reproducible catalysis.
Inasmuch as other metals are disclosed in the literature as
reducing agents for acetyloximes, zinc, copper and nickel were
examined as possible catalysts with triethyl phosphine. The results
are shown in FIG. 2. Zn(OAc).sub.2, had no catalytic effect; Zn(0),
NiCl.sub.2, CuOAc.sub.2, Ni(0) and Cu(0)) retarded the reaction.
The catalytic effect appears to be limited to iron.
The effect of temperature on the reaction was also examined. FIG. 3
shows the results. Using 50 ppm iron (as chloride or acetate salts)
and 4311 ppm elemental iron as granules, it can be seen that, at
70.degree. C. the reaction with tetralone acetyloxime is slower
than the uncatalyzed reaction at 115.degree. C., whereas at
85.degree. C. the reaction is faster than uncatalyzed at
115.degree. C., and at 115.degree. C. the reaction is complete in
about 1/6 the time. While iron at 70.degree. C. was slower than
uncatalyzed at 115.degree. C., it still went to completion at
70.degree. C., which suggests that, if one had a substrate that was
unstable at higher temperatures, the iron-catalyzed reaction would
be superior because it could be run at lower temperatures and
produce better yields of cleaner products in less time than the
corresponding uncatalyzed reaction.
* * * * *